2. Haemostasis Registry A Register to record all off-label use of recombinant activated Factor VII in Australia and New Zealand

3. Recombinant Activated Factor VII rFVIIa, NovoSeven®, eptacog alfa FVIIa is a naturally occurring initiator of haemostasis approved by TGA for the treatment of spontaneous & surgical bleeding in patients with –haemophilia A or B and with antibodies to factor VIII or factor IX –Factor VII Deficiency, –Glanzmann Thrombasthenia Licensed in Australia since 1998

4. rFVIIa outside Haemophilia Lancet 1999;354:1879

5. Life-threatening bleeding in patients with coagulation disturbances but without coagulation inhibitors Mortality rates of up to 40-60 % Coagulation disturbances in these patients are multifactorial An increased risk of thrombosis is the major potential concern ‘Investigational Use’ of rFVIIa

6. International voluntary register for off-label use set up by Novo Nordisk Highly biased case selection High level of suspicion from some clinicians No denominator Results basically unpublishable Registry pre-history

7. Haemostasis Registry 2004 NovoNordisk Australia approaches Monash University DEPM to run Registry Funded through unrestricted Educational Grant Pilot program begins in Feb 2005 at Alfred Hospital Full project launched in May 2005

8. Aims investigate the safety, efficacy and dosing of rFVIIa in investigational use monitor the extent, indications for, dosages and appropriateness of use generate information to assess cost-effectiveness and to support clinical use publish based on analyses of local experience provide data for physicians, hospitals and Regulatory Authorities

9. Governance Steering Committee – meets twice annually 2 haematology experts 2 company representatives 2 registry experts (DEPM) Project Manager Database Manager

10. Staff Chief Investigator Project Manager - Full time Administrative Assistant –1 x 0.6 –1 x 0.3 Database Management Statistical Advice

11. How does the Registry work? Hospital Contacts Registry to indicate interest  Complete Registry Set-Up Questionnaire  Ethics Approval  Begin Data Collection  Approval to collect de-identified data without patient consent

12. How does the Registry work? Patient Treated with rFVIIa at hospital  Collect Data  Submit Data  Data Verification  Reimbursement Data entry via web based system ASP.NET 2.0 + SQL Server Patients identified through pharmacy or blood bank records

13. Web Data Entry

14. Supplementary Data Obstetric Cardiac Surgery Trauma Intracranial Haemorrhage

15. Data Verification Validation on Entry –Required Fields –Value Ranges –Enabling/disabling of dependent fields –Warning Messages for Unknown or extreme values Validation on Saving –Messages for Required Fields and Value Ranges –Date Ranges –Consistency Checks Final Manual Verification

16. Haemostasis Registry Originally envisaged to include 5-6 hospitals Participating Hospitals >70 Includes all States and Territories of Australia and New Zealand Public, private, large and small hospitals Hospitals commit to provide all cases of rFVIIa use for critical bleeding in their hospital

17. 8 2 10 19 7 3 13 17 1 Participating Hospitals

18. 55 42 201 650 58 3 63 289 28 Cases Submitted 1389

19. Cases by Presentation

20. Audit – Part I Volume audit Reconcile amount purchased with cases reported Ensures compliance with “all cases” policy

21. Prince of Wales Hospital, Sydney Data collected by 2 (sometimes 3) people independently Matched and compared Numerical fields – high reproducability Text fields – essence similar but depend somewhat on understanding Audit – Part IIa

22. Audit – Part IIb Randomly Selected Hospitals with >20 cases, 5% of cases Hospitals with <20 cases grouped and 5% of total randomly selected Data re-collected by Registry Staff directly from case notes

23. Collaboration with ASCTS Cardiac Surgery HR only collects ‘cases’, not controls Looking at ASCTS to provide comparison 1.Baseline data 2.Matched Case/Control series

24. HRASCTSCABGValveCABG + Valve Other Stroke6.282.481.471.603.797.08 PE0.570.230.160.170.070.68 MI2.090.730.610.390.841.51 1. Baseline data 4.87 0.44 1.10 N.S.

25. 2. Matched Case/Control Series 525 HR Cases~ 14,000 ASCTS cases Matching for procedure type, gender, urgency and ± 5 years of age HR cases match with 0 and 2698 ASCTS cases

26. Communication with Stakeholders Newsletters and emails

27. Communication Hospital Data Report Twice annually + Annual progress report

28. Communication with Stakeholders Annual Investigator Meeting

29. Conferences Initial emphasis on recruitment and meeting people Now based on communication of results

30. Conferences

31. Publications Recombinant Activated Factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register J Isbister, L Phillips, S Dunkley, G Jankelowitz, J McNeil, P Cameron Internal Medicine Journal (in press) Recombinant Activated Factor VII in cardiac surgery: experience from the Australian and New Zealand Haemostasis Register Dunkley S, Phillips L, McCall P, Brereton J, Lindeman R, Jankelowitz G, Cameron P Annals of Thoracic Surgery (in press)

32. Strengths and Limitations Lack of Controls Missing data – especially lab results Some sub-groups have small numbers Largest numbers of cases in all therapeutic areas in the world Collecting data on entire population High level of interest from local investigators

33. Future Directions Obstetric publication Liver subcommittee More matching with other databases, eg trauma? More hospitals, more data